SDF-1与SHP-1在MDS疾病发生发展中作用的实验研究
摘要
骨髓增生异常综合征(Myelodysplastic syndrome, MDS)是血液系统的一组异质性克隆性疾病,主要表现为骨髓无效造血、外周血细胞一系或多系细胞减少,临床易转化为急性白血病。由于发病机制迄今为止尚未完全探明,故该病的诊断、分型及治疗等方面仍存在诸多悬疑。骨髓造血基质是造血系统的重要组成部分,通过产生和分泌细胞因子及细胞外基质对造血细胞的生成和分化发挥着极其重要的作用。间充质干细胞(Mesenchymal stem cell,MSC),也被称为骨髓基质细胞(Marrow stromal cell, MSC),是造血基质的重要组成部分。基质细胞衍生因子-1(SDF-1)是骨髓基质细胞表达的高效趋化因子,与其受体即表达于CD34+造血干／祖细胞(HSC/HPC)上的CXCR4特异性结合后,在HSC/HPC的归巢、骨髓定居、正常造血的维持及由骨髓动员至外周血的过程中发挥起着重要的作用。
为研究SDF-1/CXCR4在MDS发病中的作用,我们将临床骨髓标本用CD34+细胞阳性分选柱进行CD34+造血祖细胞的分选后,在60ng的SDF-1α因子作用下进行Transwell迁移实验,结果显示,低危组、对照组和高危组的迁移细胞百分比分别为(16.7±3.5)%、(18.9±2.4)%和(31.7±3.3)%,低危组与对照组相比没有明显差异,而与高危组相比则有显著差异(P<0.05)。随后对42例临床骨髓血浆标本用酶联免疫反应法测定SDF-1α因子的浓度,结果显示,在MDS低危组、高危组和正常对照组中的表达量为2301.3±413.1pg/mL、1173.3±501.1pg/mL、689.3±189.7g/mL,其组间比较P值均小于0.05,无论MDS低危组还是高危组其SDF-1α的表达量均明显高于正常对照,而MDS低危组SDF-1α的表达量明显高于高危组。同时,用流式细胞术检测分选的CD34+细胞表面CXCR4的表达,结果显示,CD34+细胞CXCR4的表达率在MDS高危组、低危组和正常对照组分别为(59.0±9.5)%、(21.4±5.0)%及(18.8±3.4)%,高危组与正常组和MDS低危组之间相比有显著差异(P<0.01),而MDS低危组与正常对照组之间没有显著差异(P>0.05)。最后,用流式细胞术测定CD34+细胞的凋亡率,结果显示,CD34+细胞凋亡率在MDS低危组、MDS高危组和正常对照组中分别为(56.8±10.2)%、(24.34±7.9)%及(18.5±8.7)%,MDS低危组与高危组或正常对照组的CD34+细胞凋亡率比较有明显差异,P值均小于0.05,而高危组与正常对照组没有明显差异,P值大于0.05。所以我们的结论是,相对于正常对照组,MDS低危组患者CD34+细胞表面表达的CXCR4的水平是正常的,但骨髓基质细胞产生的SDF-1α因子的浓度显著高于正常骨髓,导致MDS患者骨髓增生极度活跃但细胞不能动员至外周血中,并且由于凋亡率显著高于正常对照组,从而导致MDS低危组患者骨髓增生活跃但外周血细胞一系至三系细胞减少的典型临床特征；而MDS高危组,相对于低危组患者,其CD34+细胞表达CXCR4水平明显增高,骨髓基质中SDF-1α水平下降,使骨髓中的细胞容易动员到外周血中,并且其凋亡率明显下降,导致MDS高危患者原始细胞明显增高。所以SDF-1/CXCR4轴在MDS低危组中的骨髓无效造血及MDS由低危转为高危的发病机制中起重要作用。
JAK/STAT途径是一种多种细胞外信号导致靶细胞上基因表达快速改变的经典途径,该途径异常信号的传递将导致造血紊乱,与白血病等的发生有密切联系。SHP-1基因是近年来发现的抑癌基因,参与JAK/STAT途径的负性调控。启动子甲基化是SHP-1基因沉默的主要机制。为研究SHP-1在MDS发病中的作用,我们对共33例骨髓标本及1个由MDS转为AML的细胞系SKK-1进行甲基化特异PCR扩增(methylation specific PCR, MSP),结果发现在MDS低危组中SHP-1甲基化比例为18.2%,而高危组中为71.4%,SKK-1细胞系中则出现部分甲基化,正常对照组没有出现甲基化,测序分析SHP-1证实甲基化产物的正确性。我们推断SHP-1基因启动子区的甲基化可使SHP-1基因表达沉默,从而激活JAK/STAT途径参与MDS的发生发展过程。
总之,骨髓基质细胞通过SDF-1/CXCR4轴,以及造血细胞中SHP-1基因启动子甲基化激活JAK/STAT途径,参与MDS疾病的发生发展过程,在疾病演化中起重要的作用,我们可以以此作为探索MDS治疗新手段的切入点。
So far, the pathogenesis of MDS (Myelodysplastic syndrome, MDS) has not yet fully addressed, and the diagnosis, classification and treatment of this disease remain largely uncertain. Bone marrow stroma plays a very important role in the generation and differentiation of hematopoietic cells. Bone marrow stromal cell is an important component of hematopoietic stroma. Stromal cell-derived factor-1 (SDF-1) and its receptor CXCR4 play a crucial role on HSC/HPC homing, normal hematopoiesis and mobilization from the bone marrow to peripheral blood.
To study the role of SDF-1/CXCR4 in MDS, CD34 positive cells from bone marrows of patients were cultured in 60ng SDF-1 to perform transwell invasion assay. The results show that the percentage of invasive cells for low risk group, normal control group and high risk group were (16.7±3.5)%, (18.9±2.4) % and (31.7±3.3)% respectively. There are no significant differences between the control group and the low risk group, but the high-risk group is significantly high (P<0.05). And the concentration of SDF-1αin bone marrow plasma was determined with enzyme-linked immunoassay. The results show the concentration of SDF-1 a in the low risk group, the high-risk group and the control group is 2301.3±413.1pg/ml,1173.3±501.1pg/ml, and 689.3±189.7g/ml respectively and it is statistically significant between either group (P<0.05). The expression of CXCR4 in CD34-positive cells was detected by flow cytometry. CXCR4 positivity in the high risk group, the low risk group and the control group is (59.0±9.5)%, (21.4±5.0)%, and (18.8±3.4)% respectively. Compared to the low risk group or the control group, the high risk group is significantly different (P <0.01), while there is no significant difference between the low risk group and the control group (P> 0.05). The apoptosis in CD34-positive cells was also determined by flow cytometry. In the low risk group, the high risk group and the normal control group, the percentage of apoptotic cells is (56.8±10.2)%, (24.34±7.9)% and (18.5±8.7)% respectively. Compared to the high risk group or the normal control group, the apoptosis rate in the low risk group is significantly different (P<0.01). Therefore, we conclude that, compared with the normal control, the CXCR4 expression is normal in the CD34-positive cells from the MDS patients with low risk, but the bone marrow stromal cells produce excess SDF-1a factor, resulting in extremely high bone marrow apoptosis, and leading to the typical clinical phenotype. However, in the high risk MDS patients, compared with low risk patients, the number of CD34 positive cells expressing CXCR4 is significantly increased, while the bone marrow SDF-la levels decrease and the apoptosis is significantly decreased. So the SDF-1/CXCR4 axis plays a very important role in the invalid hematopoiesis in bone marrow of low risk MDS patients and in the progression from low risk to high risk.
SHP-1 gene was recently identified as a tumor suppressor gene which negatively regulates JAK/STAT pathway and promoter methylation is the main mechanism for silence of its expression. To figure out if SHP-1 plays a role in MDS, methylation specific PCR was used to detect methylation in promoter region of SHP-1 gene. In 18.2% of samples in the normal control and low risk group, SHP-1 gene was found to be methylated, while in high risk group, the percentage is increased to 71.4%, and in SKK-1 cell line SHP-1 is partially methylated. In normal control group no methylation was detected. The sequencing results of methylation PCR products further confirm the specificity of MSP. Our data suggest that promoter methylation of SHP-1 gene may activate the JAK/ STAT pathway and play a role in MDS development.
In summary, bone marrow stromal cells through SKD-1/CXCR4 axis, and promoter methylation of SHP-1 gene, may be involved in MDS development and could be targeted for MDS therapy.
为研究SDF-1/CXCR4在MDS发病中的作用,我们将临床骨髓标本用CD34+细胞阳性分选柱进行CD34+造血祖细胞的分选后,在60ng的SDF-1α因子作用下进行Transwell迁移实验,结果显示,低危组、对照组和高危组的迁移细胞百分比分别为(16.7±3.5)%、(18.9±2.4)%和(31.7±3.3)%,低危组与对照组相比没有明显差异,而与高危组相比则有显著差异(P<0.05)。随后对42例临床骨髓血浆标本用酶联免疫反应法测定SDF-1α因子的浓度,结果显示,在MDS低危组、高危组和正常对照组中的表达量为2301.3±413.1pg/mL、1173.3±501.1pg/mL、689.3±189.7g/mL,其组间比较P值均小于0.05,无论MDS低危组还是高危组其SDF-1α的表达量均明显高于正常对照,而MDS低危组SDF-1α的表达量明显高于高危组。同时,用流式细胞术检测分选的CD34+细胞表面CXCR4的表达,结果显示,CD34+细胞CXCR4的表达率在MDS高危组、低危组和正常对照组分别为(59.0±9.5)%、(21.4±5.0)%及(18.8±3.4)%,高危组与正常组和MDS低危组之间相比有显著差异(P<0.01),而MDS低危组与正常对照组之间没有显著差异(P>0.05)。最后,用流式细胞术测定CD34+细胞的凋亡率,结果显示,CD34+细胞凋亡率在MDS低危组、MDS高危组和正常对照组中分别为(56.8±10.2)%、(24.34±7.9)%及(18.5±8.7)%,MDS低危组与高危组或正常对照组的CD34+细胞凋亡率比较有明显差异,P值均小于0.05,而高危组与正常对照组没有明显差异,P值大于0.05。所以我们的结论是,相对于正常对照组,MDS低危组患者CD34+细胞表面表达的CXCR4的水平是正常的,但骨髓基质细胞产生的SDF-1α因子的浓度显著高于正常骨髓,导致MDS患者骨髓增生极度活跃但细胞不能动员至外周血中,并且由于凋亡率显著高于正常对照组,从而导致MDS低危组患者骨髓增生活跃但外周血细胞一系至三系细胞减少的典型临床特征；而MDS高危组,相对于低危组患者,其CD34+细胞表达CXCR4水平明显增高,骨髓基质中SDF-1α水平下降,使骨髓中的细胞容易动员到外周血中,并且其凋亡率明显下降,导致MDS高危患者原始细胞明显增高。所以SDF-1/CXCR4轴在MDS低危组中的骨髓无效造血及MDS由低危转为高危的发病机制中起重要作用。
JAK/STAT途径是一种多种细胞外信号导致靶细胞上基因表达快速改变的经典途径,该途径异常信号的传递将导致造血紊乱,与白血病等的发生有密切联系。SHP-1基因是近年来发现的抑癌基因,参与JAK/STAT途径的负性调控。启动子甲基化是SHP-1基因沉默的主要机制。为研究SHP-1在MDS发病中的作用,我们对共33例骨髓标本及1个由MDS转为AML的细胞系SKK-1进行甲基化特异PCR扩增(methylation specific PCR, MSP),结果发现在MDS低危组中SHP-1甲基化比例为18.2%,而高危组中为71.4%,SKK-1细胞系中则出现部分甲基化,正常对照组没有出现甲基化,测序分析SHP-1证实甲基化产物的正确性。我们推断SHP-1基因启动子区的甲基化可使SHP-1基因表达沉默,从而激活JAK/STAT途径参与MDS的发生发展过程。
总之,骨髓基质细胞通过SDF-1/CXCR4轴,以及造血细胞中SHP-1基因启动子甲基化激活JAK/STAT途径,参与MDS疾病的发生发展过程,在疾病演化中起重要的作用,我们可以以此作为探索MDS治疗新手段的切入点。
So far, the pathogenesis of MDS (Myelodysplastic syndrome, MDS) has not yet fully addressed, and the diagnosis, classification and treatment of this disease remain largely uncertain. Bone marrow stroma plays a very important role in the generation and differentiation of hematopoietic cells. Bone marrow stromal cell is an important component of hematopoietic stroma. Stromal cell-derived factor-1 (SDF-1) and its receptor CXCR4 play a crucial role on HSC/HPC homing, normal hematopoiesis and mobilization from the bone marrow to peripheral blood.
To study the role of SDF-1/CXCR4 in MDS, CD34 positive cells from bone marrows of patients were cultured in 60ng SDF-1 to perform transwell invasion assay. The results show that the percentage of invasive cells for low risk group, normal control group and high risk group were (16.7±3.5)%, (18.9±2.4) % and (31.7±3.3)% respectively. There are no significant differences between the control group and the low risk group, but the high-risk group is significantly high (P<0.05). And the concentration of SDF-1αin bone marrow plasma was determined with enzyme-linked immunoassay. The results show the concentration of SDF-1 a in the low risk group, the high-risk group and the control group is 2301.3±413.1pg/ml,1173.3±501.1pg/ml, and 689.3±189.7g/ml respectively and it is statistically significant between either group (P<0.05). The expression of CXCR4 in CD34-positive cells was detected by flow cytometry. CXCR4 positivity in the high risk group, the low risk group and the control group is (59.0±9.5)%, (21.4±5.0)%, and (18.8±3.4)% respectively. Compared to the low risk group or the control group, the high risk group is significantly different (P <0.01), while there is no significant difference between the low risk group and the control group (P> 0.05). The apoptosis in CD34-positive cells was also determined by flow cytometry. In the low risk group, the high risk group and the normal control group, the percentage of apoptotic cells is (56.8±10.2)%, (24.34±7.9)% and (18.5±8.7)% respectively. Compared to the high risk group or the normal control group, the apoptosis rate in the low risk group is significantly different (P<0.01). Therefore, we conclude that, compared with the normal control, the CXCR4 expression is normal in the CD34-positive cells from the MDS patients with low risk, but the bone marrow stromal cells produce excess SDF-1a factor, resulting in extremely high bone marrow apoptosis, and leading to the typical clinical phenotype. However, in the high risk MDS patients, compared with low risk patients, the number of CD34 positive cells expressing CXCR4 is significantly increased, while the bone marrow SDF-la levels decrease and the apoptosis is significantly decreased. So the SDF-1/CXCR4 axis plays a very important role in the invalid hematopoiesis in bone marrow of low risk MDS patients and in the progression from low risk to high risk.
SHP-1 gene was recently identified as a tumor suppressor gene which negatively regulates JAK/STAT pathway and promoter methylation is the main mechanism for silence of its expression. To figure out if SHP-1 plays a role in MDS, methylation specific PCR was used to detect methylation in promoter region of SHP-1 gene. In 18.2% of samples in the normal control and low risk group, SHP-1 gene was found to be methylated, while in high risk group, the percentage is increased to 71.4%, and in SKK-1 cell line SHP-1 is partially methylated. In normal control group no methylation was detected. The sequencing results of methylation PCR products further confirm the specificity of MSP. Our data suggest that promoter methylation of SHP-1 gene may activate the JAK/ STAT pathway and play a role in MDS development.
In summary, bone marrow stromal cells through SKD-1/CXCR4 axis, and promoter methylation of SHP-1 gene, may be involved in MDS development and could be targeted for MDS therapy.
引文
1. Parker JE, Mufti GJ. The myelodysplastic syndromes:a matter of life or death. Acta Haematol 2004; 111:78-99.
2. Flores-Figueroa E, Gutierrez-Espindola G, Montesinos JJ, et al. In vitro characterization of hematopoietic microenvironment cells from patients with myelodysplastic syndrome. Leuk Res,2002; 26(7):687-688.
3. Peter G, Christopher C, Michelle M et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood,1997,89(6):2079-2088.
4. Bennett JM, Catovsky D, Daniel MT et al. Proposals for the classification of myelodysplastic syndromes. Br J Haematol,1982,51:189-
5. Battett J, Sauntharajah Y, Molldrem J. Myelodysplastic syndrome and aplastic anemia: Distinct entities or diseases linked by a common pathophysiology? Semina Haematol 2000; 37:15-29.
6. Raza A, Meter P, Dutt D, et a. Thalidomide produces transfusion independence in long standing refractory anemias of patients with myelodysplastic syndromes. Blood 2001; 98:958-965.
7. Daskalakis M, Nguyen TT, Nguyen C, et al. Demethylation of a hypermethylated P15/INK4B gene in patients with myelodysplastic syndrome by 5-Aza-2'-deoxycytidine (decitabine) treatment.Blood 2002; 100:2957-2964.
8. Langston AA, Walling R, Winton EF, et al. Update on myelodysplastic syndromes:new approaches to classification and therapy. Senimars in Oncology 2004; 301 suppl4:72-99.
9. Deeg HJ. Marrow stroma in MDS:culprit or bystander? Leuk Res,2002; 26(7):677-686.
10.张翼鷟,达万明,骨髓增生异常综合症患者间充质干细胞的生物学特性及体外支持造血的实验研究。中国实验血.液学杂志,2005；13(5)839-842。
11. Kollet O, Spicgel A, Peled A, et al. Rapid and efficient homing of human CD34+CD38CXCR4+stem and progenitor cells to the bone marrow and spleen of NOD/SCID and NOD/B2mnull micel. Blood,2001;97(10):3283-3291.
12.张翼鷟,达万明,骨髓增生异常综合征患者间充质干细胞SDF-1基因的表达。中国实验血液学杂志,2006；14(2)：281-284.
13. Pellagatti A, Cazzola M, Giagounidis AA, et al.Gene expression profiles of CD34+ cells in my-elodysplastic syndromes:involvement of inter-feron-stimulated genes and correlation to FAB subtype and karyotype. Blood.2006;108:337-345.
14. Szpurka H, Tiu R, Murugesan G, et al. Refractory anemia with ringed sideroblasts associated with marked thrombocytosis (RARS-T), another my-eloproliferative condition characterized by JAK2V617F mutation. Blood.2006; 108:2173-2181.
15. Cheson BD, Bennett JM, Kantarjian H, et al. Re-port of an international working group to stan-dardize response criteria for myelodysplastic syn-dromes. Blood. 2000;96:3671-3674.
16. Bowen DT. Treatment strategies and issues in low/intermediate-1-risk myelodysplastic syn-drome (MDS) patients. Semin Oncol.2005;32(suppl):S16-S23.
17. List A, Kurtin S, Roe DJ, et al. Efficacy of lenalido-mide in myelodysplastic syndromes. N EnglJ Med.2005;352:549-557.
18. Creusot F, Acs G, Christman JK. Inhibition of DNA methyltransferase and induction of Friend erythroleukemia cell differentiation by 5-azacyti-dine and 5-aza-2'-deoxycytidine. J Biol Chem.1982;257:2041-2048.
19. Silverman LR, Demakos EP, Peterson BL, et al.Randomized controlled trial of azacitidine in pa-tients with the myelodysplastic syndrome:a study of the cancer and leukemia group B. J Clin Oncol.2002;20:2429-2440.
20. Schmelz K, Wagner M, Dorken B, Tamm I.5-Aza-2'-deoxycytidine induces p21 WAF expression by demethylation of p73 leading to p53-independent apoptosis in myeloid leukemia. Int J Cancer.2005; 114:683-695.
21. Maslak P, Chanel S, Camacho LH, et al. Pilot study of combination transcriptional modulation therapy with sodium phenylbutyrate and 5-azacy-tidine in patients with acute myeloid leukemia or myelodysplastic syndrome. Leukemia.2006;20:212-217.
22. Gleichmann M, Gillen C, Czardybon M, et al. Cloning and Characterization of SDF-1 gamma, a novel SDF-1 chemokine transcript with developmentally regulated expression in the nervous system. Eur J Neurosci,2000; 12:1857-1866.
23. Spiegel A, Kollet O, Peled A, et al. Unique SDF-1 induced activation of human precusor-B ALL cells as a result of altered CXCR4 expression and signaling. Blood, 2004; 103(8); 2900-2907.
24. Rombouts EJ, Pavic B, Lowenberg B, et al. Relation between CXCR4 expression, Flt3 mutations, and unfavorable prognosisi of adult acute myeloid leukemia. Blood,2004; 104:550-557.
25. Psenak O, Stomal cell-derived factor(SDF-1). Its structure and function. Cas Lek Cesk, 2001; 140:355-363.
26. Gupta SK, Pillarisetti K, Thomas RA et al. Pharmacological evidence for complex and multiple site interaction of CXCR4 with SDF-1:implications for development of selective CXCR4 antagonists. Immunol Leu,2001; 78:29-34.
27. Hatton K, Heissig B, Tashiro K, et al. Plasma elevation of stromal cell-derived factor-1 induces mobilization of mature and immature hematopoietic progenitor cells. Blood, 2001; 97:3354-3360.
28. Shen H, Cheng T, Olszak I, et al. CXCR4 desensitization is associated with tissue localization of hemopoietic progenitor cells. J Immunol,2001; 166:5027-5033.
29. Matsuda M, Morita Y, Hanamoto H, etal. CD34+ progenitors from MDS patients are unresponsive t SDF-1,despite high level of SDF-1 in bone marrow plasma. Leukemia, 2004; 18:1038-1040.
30. Wang JF, Park IW, Groopman JE, et al. Stromal cell-drived factor-1a stimulates tyrosine phosphorylation of multiple focal adhesion proteins and induces migration of hematopoietic progenitor cells:roles of phosphoinositide-3 kinase and protein kinase C. Blood,2000; 95:2505-2513.
31. Juraez J, Bradstock KF, Gottlieb DJ, et al. Effects of inhibitors of the chemokine receptor CXCR4 on acute lymphoblastic leukemiacell in vitro. Leukemia,2003; 17:1294-1300.
32. Hiroshi M, Tohru M, Tamio K et al. Establishment of a human myeloid cell line with trisomy 8 derived from overt leukemia following myelodysplastic syndrome. Hemotology,2005,90(7):981-982.
33. Voermans C, Van-Heese WP, De-Jong I, et al. Migratory behavior of leukemia cells from acute myeloid leukemia patients. Leukemia,2002; 16:650-657.
34. Kijowski J, Baj-krzyworzeka M, Majka M, et al. The SDF-1/CXCR4 axis stimulates VEGF secretion and activates integrins but does not affect proliferation and survival in lympjohematopoietic cells. Stem Cells,2001; 19:453-466.
35. Balkwill F. Chemokine biology in cancer. Semin Immunol,2003; 15:49-55.
36. Peled A, Hardan I, Traktenbrot L, et al. Immature leukemic CD34+CXCR4+cells from CML patients have lower intergrin dependent migration and adhesion in response to the chemokine SDF-1. Stem cell,2002; 20(7):259-266.
37. Campell JJ, Hedrick J, Zlotnik A, et al. Chemokines and the arrest of lymphocytes rolling under flow conditions. Science,1998; 279:381-390.
38. Zou YR, Kottmann AH, Kuroda M, et al. Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development. Nature,1998; 393:595-604.
39. Trentin L, Cabrelle A, Facco M, et al. Homeostatic chemokines drive migration of malignant B cells in patients with non-Hodgkin lymphomas. Blood,2004; 104(2);502-508.
40. Moller C, Stromberg T, Juremalm M, et al. Expression and function of chemokine receptors in human multiple myeloma. Leukemia,2003; 17(1):203-210.
41. Parker JE, Mufti GJ, Rasool F, et al. The role of apoptosis, proliferation, and the Bcl-2 related proteins in the myelodysplastic syndromes and acute myeloid leukemia secondary to MDS. Blood,2000;96:3932-3938.
42. Park JY, Strock JC, Ball DW, et al. Interleukin-lbeta can mediate growth arrest and differentiation via the leukemia inhibitory factor/JAK/STAT pathway in medullary thyroid carcinoma cells.Cytokine.2005:29(3):125-134.
43. Zhang XF, Wang JF, Matczak E, et al. Janus Kinase 2 is involved in stromal cell-derived factor-1-induced tryosine phosphrylation of focal adhesion proteins and migration of hematopoietic progenitor cell. Blood,2001;97(11)3342-3348.
44. Chor-Sang Chim, Tsz-Kin Fung, Wai-Chung Cheung, SOCS1 and SHP1 hypermethylation in multiple myeloma:implications for epigenetic activation of the Jak/STAT pathway-BLOOD,15 JUNE 2004 (103),4630-4635。
45. Reddy J, Shivapurkar N, Takahashi T,Differential methylation of genes that regulate cytokine signaling in lymphoid and hematopoietic tumors. Oncogene.2005 Jan 20;24(4):732-736.
46. Park JY, Strock JC, Ball DW, et al. Interleukin-lbeta can mediate growth arrest and differentiation via the leukemia inhibitory factor/JAK/STAT pathway in medullary thyroid carcinoma cells.Cytokine.2005; 29(3):125-134.
47. Ma X Z, Jin T, Sakac D et al. Abnormal splicing of SHP-1 protein tyrosine phosphatase in human T cells implications for lymphomagenesis. Exp Hematol,2003,31(2): 131-142.
48. Leon F, Cespon C, Franco A et al. SHP-1 expression in peripheral T cells from patients with Sezary syndrome and in the T cell line HUT-78:impliocations in JAK3-mediated signaling. Leukemia,2002,16(8):1470-1477.
49. Slack A, Cervoni N, Pinard M et al. Feedback regulation of DNA methyltransferase gene expression by methylation. Eur J Biochem,1999,264(1):191-195.
50. Bruecher-Encke B, Griffin J D, Neel B G et al. Role of the tyrosine phosphatase SHP-1 in K562 cell differentiation. Leukemia,2001,15(9):1424-1432.
51. Zhang Q, Wang H Y, Marzee M et al. STAT3-and DNA methyltransferase 1-mediated epigenetic silencing of SHP-1 tyrosine phosphatase tumour suppressor gene in maligant T lymphocytes. PNAS,2005,102(19):6948-6953.
52. Reddy J, Shivapurkar N, Takahashi T et al. Differential methylation of genes that regulate cytokine signaling in lymphoid and hematopoietic tumors. Oncogene,2005,24: 732-736.
53. Horvath CM. STAT proteins and transcriptional responses to extracellular signals. Trands Biochem Sci,2000,25(10):496-502.
54. Coggeshall K M, Nakamura K, Phee H. How do inhibitory phosphatases work. Mol Immunol,2002,39(9):521-529.
55. Haan C, Kreis S, Margue C. JAK and cytokine reportors-An intimate relationship. Biochem Pharmacol,2006,72(11):1538-1546.
56. Wu C, Sun M, Liu L et al. The function of protein tyrosine phosphatase SHP-1 in cancer. Gene,2003,306(13):1-12.
57. Rawlings JS, Rosler KM, Harrison DA. The JAK/STAT signaling pathway. J Cell Sci, 2004,117(8):1281-1283.
58. Jee SH, Chu CY, Chiu HC, et al. Interleukin-6 induced basic fibroblast growth actor-dependent angiogenesis in basal cell carcinoma cell line via JAK/STAT3 and pb-kinase/Akt pathways. J Invest Dermatol.
59. Vainchenker W, Dusa A, Constantinescu SN. JAKs in pathology:Role of Janus kinases in hematopoietic malignancies and immunodeficiencies. Semin Cell Dev Biol,2008, 19(4):385-391.
60. Verma A, Kambhampati S, Parmar S et al. Jak family of kinases in cancer. Cancer Metastasis Rev,2003,22(4):423-451.
1. Parker JE, Mufti GJ. The myelodysplastic syndromes:a matter of life or death. Acta Haematol 2004; 111:78-99.
2. Peter G, Christopher C, Michelle M et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood,1997,89(6):2079-2088.
3. Bennett JM, Catovsky D, Daniel MT et al. Proposals for the classification of myelodysplastic syndromes. Br J Haematol,1982,51:189-
4. Flores-Figueroa E, Gutierrez-Espindola G, Montesinos JJ, et al. In vitro characterization of hematopoietic microenvironment cells from patients with myelodysplastic syndrome. Leuk Res,2002; 26(7):687-688.
5. Gleichmann M, Gillen C, Czardybon M, et al. Cloning and Characterization of SDF-1 gamma, a novel SDF-1 chemokine transcript with developmentally regulated expression in the nervous system. Eur J Neurosci,2000; 12:1857-1866.
6. Rombouts EJ, Pavic B, Lowenberg B, et al. Relation between CXCR4 expression, Flt3 mutations, and unfavorable prognosisi of adult acute myeloid leukemia. Blood,2004; 104:550-557.
7. Psenak O, Stomal cell-derived factor(SDF-1). Its structure and function. Cas Lek Cesk, 2001; 140:355-363.
8. Gupta SK, Pillarisetti K, Thomas RA et al. Pharmacological evidence for complex and multiple site interaction of CXCR4 with SDF-1:implications for development of selective CXCR4 antagonists. Immunol Leu,2001; 78:29-34.
9. Hatton K, Heissig B, Tashiro K, et al. Plasma elevation of stromal cell-derived factor-1 induces mobilization of mature and immature hematopoietic progenitor cells. Blood, 2001; 97:3354-3360.
10. Wang JF, Park IW, Groopman JE, et al. Stromal cell-drived factor-la stimulates tyrosine phosphorylation of multiple focal adhesion proteins and induces migration of hematopoietic progenitor cells:roles of phosphoinositide-3 kinase and protein kinase C. Blood,2000; 95:2505-2513.
11. Voermans C, Van-Heese WP, De-Jong I, et al. Migratory behavior of leukemia cells from.acute myeloid leukemia patients. Leukemia,2002; 16:650-657.
12. Kijowski J, Baj-krzyworzeka M, Majka M, et al. The SDF-1/CXCR4 axis stimulates VEGF secretion and activates integrins but does not affect proliferation and survival in lympjohematopoietic cells. Stem Cells,2001; 19:453-466.
13. Balkwill F. Chemokine biology in cancer. Semin Immunol,2003; 15:49-55.
14. Zlotnik A, Yoshie O, Chemokine, et al. A new classfication system and their role in immunity. Immunity,2000; 12:121-126.
15. Campell JJ, Hedrick J, Zlotnik A, et al. Chemokines and the arrest of lymphocytes rolling under flow conditions. Science,1998; 279:381-390.
16. Zou YR, Kottmann AH, Kuroda M, et al. Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development. Nature,1998; 393:595-604.
17.张翼鷟,达万明,骨髓增生异常综合征患者间充质干细胞的生物学特性及体外支持造血的实验研究。中国实验血液学杂志,2005；13(5)839-842。
18. Kollet O, Spicgel A, Peled A, et al. Rapid and efficient homing of human CD34+CD38 CXCR4+stem and progenitor cells to the bone marrow and spleen of NOD/SCID and NOD/B2mnull micel. Blood,2001;97(10):3283-3291.
19.张翼鷟,达万明,骨髓增生异常综合征患者间充质干细胞SDF-1基因的表达。中国实验血液学杂志,2006；14(2)：281-284.
20. Juraez J, Bradstock KF, Gottlieb DJ, et al. Effects of inhibitors of the chemokine receptor CXCR4 on acute lymphoblastic leukemiacell in vitro. Leukemia,2003;17:1294-1300.
21. Hiroshi M, Tohru M, Tamio K et al. Establishment of a human myeloid cell line with trisomy 8 derived from overt leukemia following myelodysplastic syndrome. Hemotology,2005,90(7):981-982.
22. Shen H, Cheng T, Olszak I, et al. CXCR4 desensitization is associated with tissue localization of hemopoietic progenitor cells. J Immunol,2001; 166:5027-5033.
23. Matsuda M, Morita Y, Hanamoto H, etal. CD34+ progenitors from MDS patients are unresponsive t SDF-1,despite high level of SDF-1 in bone marrow plasma. Leukemia, 2004; 18:1038-1040.
1. Su MW, Yu CL, Burakoff SJ et al. Targeting Src homology 2 domain-containing tyrosine phosphatase (SHP-1) into lipid rafts inhibits CD3-induced T cell activation. J Immunol, 2001,166:772-780.
2. Peter G, Christopher C, Michelle M et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood,1997,89(6):2079-2088.
3. Bennett JM, Catovsky D, Daniel MT et al. Proposals for the classification of myelodysplastic syndromes. Br J Haematol,1982,51:189-
4. Parker JE, Mufti GJ. The myelodysplastic syndromes:a matter of life or death. Acta Haematol 2004; 111:78-99.
5. Flores-Figueroa E, Gutierrez-Espindola G, Montesinos JJ, et al. In vitro characterization of hematopoietic microenvironment cells from patients with myelodysplastic syndrome. Leuk Res,2002; 26(7):687-688.
6. Hiroshi M, Tohru M, Tamio K et al. Establishment of a human myeloid cell line with trisomy 8 derived from overt leukemia following myelodysplastic syndrome. Hemotology,2005,90(7):981-982.
7. Battett J, Sauntharajah Y, Molldrem J. Myelodysplastic syndrome and aplastic anemia: Distinct entities or diseases linked by a common pathophysiology? Semina Haematol 2000; 37:15-29.
8. Raza A, Meter P, Dutt D, et a. Thalidomide produces transfusion independence in long standing refractory anemias of patients with myelodysplastic syndromes. Blood 2001; 98:958-965.
9. Park JY, Strock JC, Ball DW, et al. Interleukin-1beta can mediate growth arrest and differentiation via the leukemia inhibitory factor/JAK/STAT pathway in medullary thyroid carcinoma cells.Cytokine.2005; 29(3):125-134.
10. Ma X Z, Jin T, Sakac D et al. Abnormal splicing of SHP-1 protein tyrosine phosphatase in human T cells implications for lymphomagenesis. Exp Hematol,2003,31(2): 131-142.
11. Leon F, Cespon C, Franco A et al. SHP-1 expression in peripheral T cells from patients with Sezary syndrome and in the T cell line HUT-78:impliocations in JAK3-mediated signaling. Leukemia,2002,16(8):1470-1477.
12. Slack A, Cervoni N, Pinard M et al. Feedback regulation of DNA methyltransferase gene expression by methylation. Eur J Biochem,1999,264(1):191-195.
13. Bruecher-Encke B, Griffin J D, Neel B G et al. Role of the tyrosine phosphatase SHP-1 in K562 cell differentiation. Leukemia,2001,15(9):1424-1432.
14. Zhang Q, Wang H Y, Marzee M et al. STAT3-and DNA methyltransferase 1-mediated epigenetic silencing of SHP-1 tyrosine phosphatase tumour suppressor gene in maligant T lymphocytes. PNAS,2005,102(19):6948-6953.
15. Reddy J, Shivapurkar N, Takahashi T et al. Differential methylation of genes that regulate cytokine signaling in lymphoid and hematopoietic tumors. Oncogene,2005,24: 732-736.
16. Horvath CM. STAT proteins and transcriptional responses to extracellular signals. Trands Biochem Sci,2000,25(10):496-502.
17. Imada K, Leonard WJ. The JAK-STAT pathway. Mol Immunol,2000,37(1):1-11.
18. Coggeshall K M, Nakamura K, Phee H. How do inhibitory phosphatases work. Mol Immunol,2002,39(9):521-529.
19. Haan C, Kreis S, Margue C. JAK and cytokine reportors-An intimate relationship. Biochem Pharmacol,2006,72(11):1538-1546.
20. Wu C, Sun M, Liu L et al. The function of protein tyrosine phosphatase SHP-1 in cancer. Gene,2003,306(13):1-12.
21. Rawlings JS, Rosler KM, Harrison DA. The JAK/STAT signaling pathway. J Cell Sci, 2004,117(8):1281-1283.
22. Jee SH, Chu CY, Chiu HC, et al. Interleukin-6 induced basic fibroblast growth actor-dependent angiogenesis in basal cell carcinoma cell line via JAK/STAT3 and pb-kinase/Akt pathways. J Invest Dermatol,2004,123(6):1169-1175.
23. Clarkson RW, Boland MP, Kritikou EA et al. The genes induced by signal transducer and activators of transcription (STAT)3 and STAT5 in mammary epithelial cells define the roles of these STATs in mammary development.Mol Endocrinol,2006,20(3):675-685.
24. Samuel W, Douglas J H. Inhibitors of cytokine signal transduction. J Biol Chem, 2004,279(2):821-824.
25. Vainchenker W, Dusa A, Constantinescu SN. JAKs in pathology:Role of Janus kinases in hematopoietic malignancies and immunodeficiencies. Semin Cell Dev Biol,2008, 19(4):385-391.
26. Verma A, Kambhampati S, Parmar S et al. Jak family of kinases in cancer. Cancer Metastasis Rev,2003,22(4):423-451.
1. Steensma DP, Tefferi A. The myelodysplastic syn-drome(s):a perspective and review highlighting current controversies. Leuk Res.2003;27:95-120.
2. Bennett JM, Catovsky D, Daniel MT, et al. Pro-posals for the classification of the myelodysplas-tic syndromes. Br J Haematol.1982;51:189-199.
3. Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood.2002; 100:2292-2302.
4. Pedersen-Bjergaard J, Pedersen M, Roulston D, Philip P. Different genetic pathways in leukemo-genesis for patients presenting with therapy-related myelodysplasia and therapy-related acute myeloid leukemia. Blood.1995;86:3542-3552.
5. Nimer SD, Moore MA. Effects of the leukemia-associated AML1-ETO protein on hematopoietic stem and progenitor cells. Oncogene.2004;23:4249-4254.
6. Harada H, Harada Y, Tanaka H, Kimura A, Inaba T. Implications of somatic mutations in the AML1 gene in radiation-associated and therapy-related myelodysplastic syndrome/acute myeloid leukemia. Blood.2003; 101:673-680.
7. Osato M. Point mutations in the RUNX1/AML1 gene:another actor in RUNX leukemia. Oncogene.2004;23:4284-4296.
8. Sun JY, Dagis A, Gaidulis L, et al. Detrimental effect of natural killer cell alloreactivity in T-replete hematopoietic cell transplantation (HCT) for leu-kemia patients. Biol Blood Marrow Transplant.2007; 13:197-205.
9. Mitani K. Molecular mechanisms of leukemogen-esis by AML1/EVI-1. Oncogene. 2004;23:4263-4269.
10. Kurokawa M, Mitani K, Imai Y, Ogawa S, Yazaki, Y, Hirai H. The t(3;21) fusion product, AML1/Evi-1, interacts with Smad3 and blocks transform-ing growth factor-beta-mediated growth inhibition of myeloid cells. Blood.1998;92:4003-4012.
11. Pedersen B. Anatomy of the 5q-deletion:differ-ent sex ratios and deleted 5q bands in MDS and AML. Leukemia.1996;10:1883-1890.
12. Ebert B, Pretz J, Bosco J, et al. Identification of RPS14 as a 5q—syndrome gene by RNA interfer-ence screen. Nature.2008;451:335-339.
13. Stephen D. Myelodysplastic syndromes. Blood.2008; 111:4841-4851.
14. Shivdasani RA. MicroRNAs:regulators of gene expression and cell differentiation. Blood.2006; 108:3646-3653.
15. Pellagatti A, Cazzola M, Giagounidis AA, et al.Gene expression profiles of CD34+ cells in my-elodysplastic syndromes:involvement of inter-feron-stimulated genes and correlation to FAB subtype and karyotype. Blood.2006; 108:337-345.
16. Szpurka H, Tiu R, Murugesan G, et al. Refractory anemia with ringed sideroblasts associated with marked thrombocytosis (RARS-T), another my-eloproliferative condition characterized by JAK2V617F mutation. Blood.2006; 108:2173-2181.
17. Cheson BD, Bennett JM, Kantarjian H, et al. Re-port of an international working group to stan-dardize response criteria for myelodysplastic syn-dromes. Blood.2000;96:3671-3674.
18. Bowen DT. Treatment strategies and issues in low/intermediate-1-risk myelodysplastic syn-drome (MDS) patients. Semin Oncol.2005;32(suppl):S16-S23.
19. List A, Kurtin S, Roe DJ, et al. Efficacy of lenalido-mide in myelodysplastic syndromes. N EnglJ Med.2005;352:549-557.
20. Creusot F, Acs G, Christman JK. Inhibition of DNA methyltransferase and induction of Friend erythroleukemia cell differentiation by 5-azacyti-dine and 5-aza-2'-deoxycytidine. J Biol Chem.1982;257:2041-2048.
21. Silverman LR, Demakos EP, Peterson BL, et al.Randomized controlled trial of azacitidine in pa-tients with the myelodysplastic syndrome:a study of the cancer and leukemia group B. J Clin Oncol.2002;20:2429-2440.
22. Schmelz K, Wagner M, Dorken B, Tamm I.5-Aza-2'-deoxycytidine induces p21 WAF expression by demethylation of p73 leading to p53-independent apoptosis in myeloid leukemia. Int J Cancer.2005;114:683-695.
23. Maslak P, Chanel S, Camacho LH, et al. Pilot study of combination transcriptional modulation therapy with sodium phenylbutyrate and 5-azacy-tidine in patients with acute myeloid leukemia or myelodysplastic syndrome. Leukemia.2006;20:212-217.
24. Rice JC, Allis CD. Histone methylation versus histone acetylation:new insights into epigenetic regulation. Curr Opin Cell Biol.2001;13:263-273.
25. Wang GG, Cai L, Pasillas MP, Kamps MP.NUP98-NSD1 links H3K36 methylation to Hox-A gene activation and leukaemogenesis. Nat Cell Biol.2007;9:804-812.
26. Martin C, Zhang Y. The diverse functions of his-tone lysine methylation. Nat Rev Mol Cell Biol.2005;6:838-849.
27. Milne TA, Briggs SD, Brock HW, et al. MLL tar-gets SET domain methyltransferase activity to Hox gene promoters. Mol Cell.2002; 10:1107-1117.
2. Flores-Figueroa E, Gutierrez-Espindola G, Montesinos JJ, et al. In vitro characterization of hematopoietic microenvironment cells from patients with myelodysplastic syndrome. Leuk Res,2002; 26(7):687-688.
3. Peter G, Christopher C, Michelle M et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood,1997,89(6):2079-2088.
4. Bennett JM, Catovsky D, Daniel MT et al. Proposals for the classification of myelodysplastic syndromes. Br J Haematol,1982,51:189-
5. Battett J, Sauntharajah Y, Molldrem J. Myelodysplastic syndrome and aplastic anemia: Distinct entities or diseases linked by a common pathophysiology? Semina Haematol 2000; 37:15-29.
6. Raza A, Meter P, Dutt D, et a. Thalidomide produces transfusion independence in long standing refractory anemias of patients with myelodysplastic syndromes. Blood 2001; 98:958-965.
7. Daskalakis M, Nguyen TT, Nguyen C, et al. Demethylation of a hypermethylated P15/INK4B gene in patients with myelodysplastic syndrome by 5-Aza-2'-deoxycytidine (decitabine) treatment.Blood 2002; 100:2957-2964.
8. Langston AA, Walling R, Winton EF, et al. Update on myelodysplastic syndromes:new approaches to classification and therapy. Senimars in Oncology 2004; 301 suppl4:72-99.
9. Deeg HJ. Marrow stroma in MDS:culprit or bystander? Leuk Res,2002; 26(7):677-686.
10.张翼鷟,达万明,骨髓增生异常综合症患者间充质干细胞的生物学特性及体外支持造血的实验研究。中国实验血.液学杂志,2005；13(5)839-842。
11. Kollet O, Spicgel A, Peled A, et al. Rapid and efficient homing of human CD34+CD38CXCR4+stem and progenitor cells to the bone marrow and spleen of NOD/SCID and NOD/B2mnull micel. Blood,2001;97(10):3283-3291.
12.张翼鷟,达万明,骨髓增生异常综合征患者间充质干细胞SDF-1基因的表达。中国实验血液学杂志,2006；14(2)：281-284.
13. Pellagatti A, Cazzola M, Giagounidis AA, et al.Gene expression profiles of CD34+ cells in my-elodysplastic syndromes:involvement of inter-feron-stimulated genes and correlation to FAB subtype and karyotype. Blood.2006;108:337-345.
14. Szpurka H, Tiu R, Murugesan G, et al. Refractory anemia with ringed sideroblasts associated with marked thrombocytosis (RARS-T), another my-eloproliferative condition characterized by JAK2V617F mutation. Blood.2006; 108:2173-2181.
15. Cheson BD, Bennett JM, Kantarjian H, et al. Re-port of an international working group to stan-dardize response criteria for myelodysplastic syn-dromes. Blood. 2000;96:3671-3674.
16. Bowen DT. Treatment strategies and issues in low/intermediate-1-risk myelodysplastic syn-drome (MDS) patients. Semin Oncol.2005;32(suppl):S16-S23.
17. List A, Kurtin S, Roe DJ, et al. Efficacy of lenalido-mide in myelodysplastic syndromes. N EnglJ Med.2005;352:549-557.
18. Creusot F, Acs G, Christman JK. Inhibition of DNA methyltransferase and induction of Friend erythroleukemia cell differentiation by 5-azacyti-dine and 5-aza-2'-deoxycytidine. J Biol Chem.1982;257:2041-2048.
19. Silverman LR, Demakos EP, Peterson BL, et al.Randomized controlled trial of azacitidine in pa-tients with the myelodysplastic syndrome:a study of the cancer and leukemia group B. J Clin Oncol.2002;20:2429-2440.
20. Schmelz K, Wagner M, Dorken B, Tamm I.5-Aza-2'-deoxycytidine induces p21 WAF expression by demethylation of p73 leading to p53-independent apoptosis in myeloid leukemia. Int J Cancer.2005; 114:683-695.
21. Maslak P, Chanel S, Camacho LH, et al. Pilot study of combination transcriptional modulation therapy with sodium phenylbutyrate and 5-azacy-tidine in patients with acute myeloid leukemia or myelodysplastic syndrome. Leukemia.2006;20:212-217.
22. Gleichmann M, Gillen C, Czardybon M, et al. Cloning and Characterization of SDF-1 gamma, a novel SDF-1 chemokine transcript with developmentally regulated expression in the nervous system. Eur J Neurosci,2000; 12:1857-1866.
23. Spiegel A, Kollet O, Peled A, et al. Unique SDF-1 induced activation of human precusor-B ALL cells as a result of altered CXCR4 expression and signaling. Blood, 2004; 103(8); 2900-2907.
24. Rombouts EJ, Pavic B, Lowenberg B, et al. Relation between CXCR4 expression, Flt3 mutations, and unfavorable prognosisi of adult acute myeloid leukemia. Blood,2004; 104:550-557.
25. Psenak O, Stomal cell-derived factor(SDF-1). Its structure and function. Cas Lek Cesk, 2001; 140:355-363.
26. Gupta SK, Pillarisetti K, Thomas RA et al. Pharmacological evidence for complex and multiple site interaction of CXCR4 with SDF-1:implications for development of selective CXCR4 antagonists. Immunol Leu,2001; 78:29-34.
27. Hatton K, Heissig B, Tashiro K, et al. Plasma elevation of stromal cell-derived factor-1 induces mobilization of mature and immature hematopoietic progenitor cells. Blood, 2001; 97:3354-3360.
28. Shen H, Cheng T, Olszak I, et al. CXCR4 desensitization is associated with tissue localization of hemopoietic progenitor cells. J Immunol,2001; 166:5027-5033.
29. Matsuda M, Morita Y, Hanamoto H, etal. CD34+ progenitors from MDS patients are unresponsive t SDF-1,despite high level of SDF-1 in bone marrow plasma. Leukemia, 2004; 18:1038-1040.
30. Wang JF, Park IW, Groopman JE, et al. Stromal cell-drived factor-1a stimulates tyrosine phosphorylation of multiple focal adhesion proteins and induces migration of hematopoietic progenitor cells:roles of phosphoinositide-3 kinase and protein kinase C. Blood,2000; 95:2505-2513.
31. Juraez J, Bradstock KF, Gottlieb DJ, et al. Effects of inhibitors of the chemokine receptor CXCR4 on acute lymphoblastic leukemiacell in vitro. Leukemia,2003; 17:1294-1300.
32. Hiroshi M, Tohru M, Tamio K et al. Establishment of a human myeloid cell line with trisomy 8 derived from overt leukemia following myelodysplastic syndrome. Hemotology,2005,90(7):981-982.
33. Voermans C, Van-Heese WP, De-Jong I, et al. Migratory behavior of leukemia cells from acute myeloid leukemia patients. Leukemia,2002; 16:650-657.
34. Kijowski J, Baj-krzyworzeka M, Majka M, et al. The SDF-1/CXCR4 axis stimulates VEGF secretion and activates integrins but does not affect proliferation and survival in lympjohematopoietic cells. Stem Cells,2001; 19:453-466.
35. Balkwill F. Chemokine biology in cancer. Semin Immunol,2003; 15:49-55.
36. Peled A, Hardan I, Traktenbrot L, et al. Immature leukemic CD34+CXCR4+cells from CML patients have lower intergrin dependent migration and adhesion in response to the chemokine SDF-1. Stem cell,2002; 20(7):259-266.
37. Campell JJ, Hedrick J, Zlotnik A, et al. Chemokines and the arrest of lymphocytes rolling under flow conditions. Science,1998; 279:381-390.
38. Zou YR, Kottmann AH, Kuroda M, et al. Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development. Nature,1998; 393:595-604.
39. Trentin L, Cabrelle A, Facco M, et al. Homeostatic chemokines drive migration of malignant B cells in patients with non-Hodgkin lymphomas. Blood,2004; 104(2);502-508.
40. Moller C, Stromberg T, Juremalm M, et al. Expression and function of chemokine receptors in human multiple myeloma. Leukemia,2003; 17(1):203-210.
41. Parker JE, Mufti GJ, Rasool F, et al. The role of apoptosis, proliferation, and the Bcl-2 related proteins in the myelodysplastic syndromes and acute myeloid leukemia secondary to MDS. Blood,2000;96:3932-3938.
42. Park JY, Strock JC, Ball DW, et al. Interleukin-lbeta can mediate growth arrest and differentiation via the leukemia inhibitory factor/JAK/STAT pathway in medullary thyroid carcinoma cells.Cytokine.2005:29(3):125-134.
43. Zhang XF, Wang JF, Matczak E, et al. Janus Kinase 2 is involved in stromal cell-derived factor-1-induced tryosine phosphrylation of focal adhesion proteins and migration of hematopoietic progenitor cell. Blood,2001;97(11)3342-3348.
44. Chor-Sang Chim, Tsz-Kin Fung, Wai-Chung Cheung, SOCS1 and SHP1 hypermethylation in multiple myeloma:implications for epigenetic activation of the Jak/STAT pathway-BLOOD,15 JUNE 2004 (103),4630-4635。
45. Reddy J, Shivapurkar N, Takahashi T,Differential methylation of genes that regulate cytokine signaling in lymphoid and hematopoietic tumors. Oncogene.2005 Jan 20;24(4):732-736.
46. Park JY, Strock JC, Ball DW, et al. Interleukin-lbeta can mediate growth arrest and differentiation via the leukemia inhibitory factor/JAK/STAT pathway in medullary thyroid carcinoma cells.Cytokine.2005; 29(3):125-134.
47. Ma X Z, Jin T, Sakac D et al. Abnormal splicing of SHP-1 protein tyrosine phosphatase in human T cells implications for lymphomagenesis. Exp Hematol,2003,31(2): 131-142.
48. Leon F, Cespon C, Franco A et al. SHP-1 expression in peripheral T cells from patients with Sezary syndrome and in the T cell line HUT-78:impliocations in JAK3-mediated signaling. Leukemia,2002,16(8):1470-1477.
49. Slack A, Cervoni N, Pinard M et al. Feedback regulation of DNA methyltransferase gene expression by methylation. Eur J Biochem,1999,264(1):191-195.
50. Bruecher-Encke B, Griffin J D, Neel B G et al. Role of the tyrosine phosphatase SHP-1 in K562 cell differentiation. Leukemia,2001,15(9):1424-1432.
51. Zhang Q, Wang H Y, Marzee M et al. STAT3-and DNA methyltransferase 1-mediated epigenetic silencing of SHP-1 tyrosine phosphatase tumour suppressor gene in maligant T lymphocytes. PNAS,2005,102(19):6948-6953.
52. Reddy J, Shivapurkar N, Takahashi T et al. Differential methylation of genes that regulate cytokine signaling in lymphoid and hematopoietic tumors. Oncogene,2005,24: 732-736.
53. Horvath CM. STAT proteins and transcriptional responses to extracellular signals. Trands Biochem Sci,2000,25(10):496-502.
54. Coggeshall K M, Nakamura K, Phee H. How do inhibitory phosphatases work. Mol Immunol,2002,39(9):521-529.
55. Haan C, Kreis S, Margue C. JAK and cytokine reportors-An intimate relationship. Biochem Pharmacol,2006,72(11):1538-1546.
56. Wu C, Sun M, Liu L et al. The function of protein tyrosine phosphatase SHP-1 in cancer. Gene,2003,306(13):1-12.
57. Rawlings JS, Rosler KM, Harrison DA. The JAK/STAT signaling pathway. J Cell Sci, 2004,117(8):1281-1283.
58. Jee SH, Chu CY, Chiu HC, et al. Interleukin-6 induced basic fibroblast growth actor-dependent angiogenesis in basal cell carcinoma cell line via JAK/STAT3 and pb-kinase/Akt pathways. J Invest Dermatol.
59. Vainchenker W, Dusa A, Constantinescu SN. JAKs in pathology:Role of Janus kinases in hematopoietic malignancies and immunodeficiencies. Semin Cell Dev Biol,2008, 19(4):385-391.
60. Verma A, Kambhampati S, Parmar S et al. Jak family of kinases in cancer. Cancer Metastasis Rev,2003,22(4):423-451.
1. Parker JE, Mufti GJ. The myelodysplastic syndromes:a matter of life or death. Acta Haematol 2004; 111:78-99.
2. Peter G, Christopher C, Michelle M et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood,1997,89(6):2079-2088.
3. Bennett JM, Catovsky D, Daniel MT et al. Proposals for the classification of myelodysplastic syndromes. Br J Haematol,1982,51:189-
4. Flores-Figueroa E, Gutierrez-Espindola G, Montesinos JJ, et al. In vitro characterization of hematopoietic microenvironment cells from patients with myelodysplastic syndrome. Leuk Res,2002; 26(7):687-688.
5. Gleichmann M, Gillen C, Czardybon M, et al. Cloning and Characterization of SDF-1 gamma, a novel SDF-1 chemokine transcript with developmentally regulated expression in the nervous system. Eur J Neurosci,2000; 12:1857-1866.
6. Rombouts EJ, Pavic B, Lowenberg B, et al. Relation between CXCR4 expression, Flt3 mutations, and unfavorable prognosisi of adult acute myeloid leukemia. Blood,2004; 104:550-557.
7. Psenak O, Stomal cell-derived factor(SDF-1). Its structure and function. Cas Lek Cesk, 2001; 140:355-363.
8. Gupta SK, Pillarisetti K, Thomas RA et al. Pharmacological evidence for complex and multiple site interaction of CXCR4 with SDF-1:implications for development of selective CXCR4 antagonists. Immunol Leu,2001; 78:29-34.
9. Hatton K, Heissig B, Tashiro K, et al. Plasma elevation of stromal cell-derived factor-1 induces mobilization of mature and immature hematopoietic progenitor cells. Blood, 2001; 97:3354-3360.
10. Wang JF, Park IW, Groopman JE, et al. Stromal cell-drived factor-la stimulates tyrosine phosphorylation of multiple focal adhesion proteins and induces migration of hematopoietic progenitor cells:roles of phosphoinositide-3 kinase and protein kinase C. Blood,2000; 95:2505-2513.
11. Voermans C, Van-Heese WP, De-Jong I, et al. Migratory behavior of leukemia cells from.acute myeloid leukemia patients. Leukemia,2002; 16:650-657.
12. Kijowski J, Baj-krzyworzeka M, Majka M, et al. The SDF-1/CXCR4 axis stimulates VEGF secretion and activates integrins but does not affect proliferation and survival in lympjohematopoietic cells. Stem Cells,2001; 19:453-466.
13. Balkwill F. Chemokine biology in cancer. Semin Immunol,2003; 15:49-55.
14. Zlotnik A, Yoshie O, Chemokine, et al. A new classfication system and their role in immunity. Immunity,2000; 12:121-126.
15. Campell JJ, Hedrick J, Zlotnik A, et al. Chemokines and the arrest of lymphocytes rolling under flow conditions. Science,1998; 279:381-390.
16. Zou YR, Kottmann AH, Kuroda M, et al. Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development. Nature,1998; 393:595-604.
17.张翼鷟,达万明,骨髓增生异常综合征患者间充质干细胞的生物学特性及体外支持造血的实验研究。中国实验血液学杂志,2005；13(5)839-842。
18. Kollet O, Spicgel A, Peled A, et al. Rapid and efficient homing of human CD34+CD38 CXCR4+stem and progenitor cells to the bone marrow and spleen of NOD/SCID and NOD/B2mnull micel. Blood,2001;97(10):3283-3291.
19.张翼鷟,达万明,骨髓增生异常综合征患者间充质干细胞SDF-1基因的表达。中国实验血液学杂志,2006；14(2)：281-284.
20. Juraez J, Bradstock KF, Gottlieb DJ, et al. Effects of inhibitors of the chemokine receptor CXCR4 on acute lymphoblastic leukemiacell in vitro. Leukemia,2003;17:1294-1300.
21. Hiroshi M, Tohru M, Tamio K et al. Establishment of a human myeloid cell line with trisomy 8 derived from overt leukemia following myelodysplastic syndrome. Hemotology,2005,90(7):981-982.
22. Shen H, Cheng T, Olszak I, et al. CXCR4 desensitization is associated with tissue localization of hemopoietic progenitor cells. J Immunol,2001; 166:5027-5033.
23. Matsuda M, Morita Y, Hanamoto H, etal. CD34+ progenitors from MDS patients are unresponsive t SDF-1,despite high level of SDF-1 in bone marrow plasma. Leukemia, 2004; 18:1038-1040.
1. Su MW, Yu CL, Burakoff SJ et al. Targeting Src homology 2 domain-containing tyrosine phosphatase (SHP-1) into lipid rafts inhibits CD3-induced T cell activation. J Immunol, 2001,166:772-780.
2. Peter G, Christopher C, Michelle M et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood,1997,89(6):2079-2088.
3. Bennett JM, Catovsky D, Daniel MT et al. Proposals for the classification of myelodysplastic syndromes. Br J Haematol,1982,51:189-
4. Parker JE, Mufti GJ. The myelodysplastic syndromes:a matter of life or death. Acta Haematol 2004; 111:78-99.
5. Flores-Figueroa E, Gutierrez-Espindola G, Montesinos JJ, et al. In vitro characterization of hematopoietic microenvironment cells from patients with myelodysplastic syndrome. Leuk Res,2002; 26(7):687-688.
6. Hiroshi M, Tohru M, Tamio K et al. Establishment of a human myeloid cell line with trisomy 8 derived from overt leukemia following myelodysplastic syndrome. Hemotology,2005,90(7):981-982.
7. Battett J, Sauntharajah Y, Molldrem J. Myelodysplastic syndrome and aplastic anemia: Distinct entities or diseases linked by a common pathophysiology? Semina Haematol 2000; 37:15-29.
8. Raza A, Meter P, Dutt D, et a. Thalidomide produces transfusion independence in long standing refractory anemias of patients with myelodysplastic syndromes. Blood 2001; 98:958-965.
9. Park JY, Strock JC, Ball DW, et al. Interleukin-1beta can mediate growth arrest and differentiation via the leukemia inhibitory factor/JAK/STAT pathway in medullary thyroid carcinoma cells.Cytokine.2005; 29(3):125-134.
10. Ma X Z, Jin T, Sakac D et al. Abnormal splicing of SHP-1 protein tyrosine phosphatase in human T cells implications for lymphomagenesis. Exp Hematol,2003,31(2): 131-142.
11. Leon F, Cespon C, Franco A et al. SHP-1 expression in peripheral T cells from patients with Sezary syndrome and in the T cell line HUT-78:impliocations in JAK3-mediated signaling. Leukemia,2002,16(8):1470-1477.
12. Slack A, Cervoni N, Pinard M et al. Feedback regulation of DNA methyltransferase gene expression by methylation. Eur J Biochem,1999,264(1):191-195.
13. Bruecher-Encke B, Griffin J D, Neel B G et al. Role of the tyrosine phosphatase SHP-1 in K562 cell differentiation. Leukemia,2001,15(9):1424-1432.
14. Zhang Q, Wang H Y, Marzee M et al. STAT3-and DNA methyltransferase 1-mediated epigenetic silencing of SHP-1 tyrosine phosphatase tumour suppressor gene in maligant T lymphocytes. PNAS,2005,102(19):6948-6953.
15. Reddy J, Shivapurkar N, Takahashi T et al. Differential methylation of genes that regulate cytokine signaling in lymphoid and hematopoietic tumors. Oncogene,2005,24: 732-736.
16. Horvath CM. STAT proteins and transcriptional responses to extracellular signals. Trands Biochem Sci,2000,25(10):496-502.
17. Imada K, Leonard WJ. The JAK-STAT pathway. Mol Immunol,2000,37(1):1-11.
18. Coggeshall K M, Nakamura K, Phee H. How do inhibitory phosphatases work. Mol Immunol,2002,39(9):521-529.
19. Haan C, Kreis S, Margue C. JAK and cytokine reportors-An intimate relationship. Biochem Pharmacol,2006,72(11):1538-1546.
20. Wu C, Sun M, Liu L et al. The function of protein tyrosine phosphatase SHP-1 in cancer. Gene,2003,306(13):1-12.
21. Rawlings JS, Rosler KM, Harrison DA. The JAK/STAT signaling pathway. J Cell Sci, 2004,117(8):1281-1283.
22. Jee SH, Chu CY, Chiu HC, et al. Interleukin-6 induced basic fibroblast growth actor-dependent angiogenesis in basal cell carcinoma cell line via JAK/STAT3 and pb-kinase/Akt pathways. J Invest Dermatol,2004,123(6):1169-1175.
23. Clarkson RW, Boland MP, Kritikou EA et al. The genes induced by signal transducer and activators of transcription (STAT)3 and STAT5 in mammary epithelial cells define the roles of these STATs in mammary development.Mol Endocrinol,2006,20(3):675-685.
24. Samuel W, Douglas J H. Inhibitors of cytokine signal transduction. J Biol Chem, 2004,279(2):821-824.
25. Vainchenker W, Dusa A, Constantinescu SN. JAKs in pathology:Role of Janus kinases in hematopoietic malignancies and immunodeficiencies. Semin Cell Dev Biol,2008, 19(4):385-391.
26. Verma A, Kambhampati S, Parmar S et al. Jak family of kinases in cancer. Cancer Metastasis Rev,2003,22(4):423-451.
1. Steensma DP, Tefferi A. The myelodysplastic syn-drome(s):a perspective and review highlighting current controversies. Leuk Res.2003;27:95-120.
2. Bennett JM, Catovsky D, Daniel MT, et al. Pro-posals for the classification of the myelodysplas-tic syndromes. Br J Haematol.1982;51:189-199.
3. Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood.2002; 100:2292-2302.
4. Pedersen-Bjergaard J, Pedersen M, Roulston D, Philip P. Different genetic pathways in leukemo-genesis for patients presenting with therapy-related myelodysplasia and therapy-related acute myeloid leukemia. Blood.1995;86:3542-3552.
5. Nimer SD, Moore MA. Effects of the leukemia-associated AML1-ETO protein on hematopoietic stem and progenitor cells. Oncogene.2004;23:4249-4254.
6. Harada H, Harada Y, Tanaka H, Kimura A, Inaba T. Implications of somatic mutations in the AML1 gene in radiation-associated and therapy-related myelodysplastic syndrome/acute myeloid leukemia. Blood.2003; 101:673-680.
7. Osato M. Point mutations in the RUNX1/AML1 gene:another actor in RUNX leukemia. Oncogene.2004;23:4284-4296.
8. Sun JY, Dagis A, Gaidulis L, et al. Detrimental effect of natural killer cell alloreactivity in T-replete hematopoietic cell transplantation (HCT) for leu-kemia patients. Biol Blood Marrow Transplant.2007; 13:197-205.
9. Mitani K. Molecular mechanisms of leukemogen-esis by AML1/EVI-1. Oncogene. 2004;23:4263-4269.
10. Kurokawa M, Mitani K, Imai Y, Ogawa S, Yazaki, Y, Hirai H. The t(3;21) fusion product, AML1/Evi-1, interacts with Smad3 and blocks transform-ing growth factor-beta-mediated growth inhibition of myeloid cells. Blood.1998;92:4003-4012.
11. Pedersen B. Anatomy of the 5q-deletion:differ-ent sex ratios and deleted 5q bands in MDS and AML. Leukemia.1996;10:1883-1890.
12. Ebert B, Pretz J, Bosco J, et al. Identification of RPS14 as a 5q—syndrome gene by RNA interfer-ence screen. Nature.2008;451:335-339.
13. Stephen D. Myelodysplastic syndromes. Blood.2008; 111:4841-4851.
14. Shivdasani RA. MicroRNAs:regulators of gene expression and cell differentiation. Blood.2006; 108:3646-3653.
15. Pellagatti A, Cazzola M, Giagounidis AA, et al.Gene expression profiles of CD34+ cells in my-elodysplastic syndromes:involvement of inter-feron-stimulated genes and correlation to FAB subtype and karyotype. Blood.2006; 108:337-345.
16. Szpurka H, Tiu R, Murugesan G, et al. Refractory anemia with ringed sideroblasts associated with marked thrombocytosis (RARS-T), another my-eloproliferative condition characterized by JAK2V617F mutation. Blood.2006; 108:2173-2181.
17. Cheson BD, Bennett JM, Kantarjian H, et al. Re-port of an international working group to stan-dardize response criteria for myelodysplastic syn-dromes. Blood.2000;96:3671-3674.
18. Bowen DT. Treatment strategies and issues in low/intermediate-1-risk myelodysplastic syn-drome (MDS) patients. Semin Oncol.2005;32(suppl):S16-S23.
19. List A, Kurtin S, Roe DJ, et al. Efficacy of lenalido-mide in myelodysplastic syndromes. N EnglJ Med.2005;352:549-557.
20. Creusot F, Acs G, Christman JK. Inhibition of DNA methyltransferase and induction of Friend erythroleukemia cell differentiation by 5-azacyti-dine and 5-aza-2'-deoxycytidine. J Biol Chem.1982;257:2041-2048.
21. Silverman LR, Demakos EP, Peterson BL, et al.Randomized controlled trial of azacitidine in pa-tients with the myelodysplastic syndrome:a study of the cancer and leukemia group B. J Clin Oncol.2002;20:2429-2440.
22. Schmelz K, Wagner M, Dorken B, Tamm I.5-Aza-2'-deoxycytidine induces p21 WAF expression by demethylation of p73 leading to p53-independent apoptosis in myeloid leukemia. Int J Cancer.2005;114:683-695.
23. Maslak P, Chanel S, Camacho LH, et al. Pilot study of combination transcriptional modulation therapy with sodium phenylbutyrate and 5-azacy-tidine in patients with acute myeloid leukemia or myelodysplastic syndrome. Leukemia.2006;20:212-217.
24. Rice JC, Allis CD. Histone methylation versus histone acetylation:new insights into epigenetic regulation. Curr Opin Cell Biol.2001;13:263-273.
25. Wang GG, Cai L, Pasillas MP, Kamps MP.NUP98-NSD1 links H3K36 methylation to Hox-A gene activation and leukaemogenesis. Nat Cell Biol.2007;9:804-812.
26. Martin C, Zhang Y. The diverse functions of his-tone lysine methylation. Nat Rev Mol Cell Biol.2005;6:838-849.
27. Milne TA, Briggs SD, Brock HW, et al. MLL tar-gets SET domain methyltransferase activity to Hox gene promoters. Mol Cell.2002; 10:1107-1117.
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |